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ABSTRACT
Introduction: Schizophrenia is a debilitating condition with three main symptom domains: positive, negative, and cognitive. Approximately one-third of persons with schizophrenia will fail to respond to treatment. Growing evidence suggests that treatment-resistant (refractory) schizophrenia (TRS) may be a distinct condition from treatment-respondent schizophrenia. There is limited evidence on effective treatments for TRS, and a lack of standardized diagnostic criteria for TRS has hampered research.
Areas covered: A literature search was conducted using Pubmed.gov and the EMBASE literature database. The authors discuss the pragmatic definitions of TRS and review treatments consisting of antipsychotic monotherapy and augmentation strategies.
Expert opinion: Currently available first-line antipsychotic medications are generally effective at treating the positive symptoms of schizophrenia, leaving residual negative and cognitive symptoms. Before diagnosing TRS, rule out any pharmacodynamic or pharmacokinetic failures. Most evidence supports clozapine as having the most efficacy for TRS. If clozapine is used, it should be optimized, and serum levels should be at least 350–420 ng/ml. If clozapine is unable to be tolerated, some evidence suggests olanzapine at dosages up to 40mg/day can be useful. Augmentation strategies have weak evidence. Tailoring treatment to the specific domain is the preferred approach, and the use of a structured assessment/outcome measure is encouraged.
Article highlights
Approximately one-third of patients with schizophrenia will have an insufficient response to treatment.
Currently available antipsychotic medications are generally effective at treating the positive symptoms of schizophrenia, often leaving residual negative and cognitive symptoms.
A lack of consensus diagnostic criteria has hampered research into treatment-resistant (treatment-refractory) schizophrenia (TRS).
Most available evidence supports clozapine as having the most efficacy for TRS, but it is underutilized and under optimized.
Augmentation strategies for antipsychotics have weak evidence supporting their use, and treatment should be tailored to the specific residual symptom.
The use of a structured measure such as the Clinician-Rated Dimensions of Psychosis Symptom Severity scale is encouraged.
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Declaration of interest
L Citrome declares that, in the past 5 years, he has engaged in collaborative research with and/or has received consulting or speaking fees from Acadia, Alkermes, Alexza, Allergan, AstraZeneca, Avaniir, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly and Company, Forum, Genentech, Intra-Cellular Therapies, Janssen Pharmaceuticals, Jazz Pharmaceuticals, Lundbeck, Merck & Co., Medivation, Mylan, Neurocrine Biosciences, Novartis, Noven, Otsuka, Pfizer Inc, Indivior/Reckitt Benckiser Reviva, Shire, Sunovion, Takeda, Teva Pharmaceuticals, Valeant Pharmaceuticals (Bausch Health) and Vanda. Additionally, they declare that they have stocks (a small number of shares of common stock) from Bristol-Myers Squibb, Eli Lilly and Company, Johnson and Johnson, Merck and Co., and Pfizer which were purchased over 10 years ago. Finally, they declare that they have received royalties from Wiley, UpToDate and Springer Healthcare. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
Reviewer disclosures
One referee declares that in the last 3 years, they have been a member of scientific advisory boards for Sunovion, Otsuka/Lundbeck and Newron Pharmaceuticals. They have also received speaker fees from Janssen Pharmaceuticals.